Process for preparing a directly compressible solid dosage form containing microcrystalline cellulose

ABSTRACT

The present invention provides an improved process for the preparation of a agglomerated solid dosage form, comprising preparing an aqueous slurry of microcrystalline cellulose and a microcrystalline cellulose compressibility augmenting agent and an active agent. The augmenting agent is capable of physically restricting the proximity of the interface between adjacent cellulose surfaces and/or inhibiting interactions between adjacent cellulose surfaces, for example, via the creation of a hydrophobic boundary at cellulose surfaces. The resulting aqueous slurry is dried in a manner which inhibits quasi-hornification, thereby obtaining an agglomerated material which is directly compressible into a solid dosage form.

This application claims the benefit of U.S. Provisional Application No.60/019,546 filed Jun. 10, 1996.

BACKGROUND OF THE INVENTION

The present invention relates to a novel excipient for use in themanufacture of pharmaceuticals, and in particular, solid dosage formssuch as tablets which include one or more active ingredients.

In order to prepare a solid dosage form containing one or more activeingredients (such as drugs), it is necessary that the material to becompressed into the dosage form possess certain physical characteristicswhich lend themselves to processing in such a manner. Among otherthings, the material to be compressed must be free-flowing, must belubricated, and, importantly, must possess sufficient cohesiveness toinsure that the solid dosage form remains intact after compression.

In the case of tablets, the tablet is formed by pressure being appliedto the material to be tableted on a tablet press. A tablet pressincludes a lower punch which fits into a die from the bottom and a upperpunch having a corresponding shape and dimension which enters the diecavity from the top after the tableting material fills the die cavity.The tablet is formed by pressure applied on the lower and upper punches.The ability of the material to flow freely into the die is important inorder to insure that there is a uniform filling of the die and acontinuous movement of the material from the source of the material,e.g. a feeder hopper. The lubricity of the material is crucial in thepreparation of the solid dosage forms since the compressed material mustbe readily ejected from the punch faces.

Since most drugs have none or only some of these properties, methods oftablet formulation have been developed in order to impart thesedesirable characteristics to the material(s) which is to be compressedinto a solid dosage form. Typically, the material to be compressed intoa solid dosage form includes one or more excipients which impart thefree-flowing, lubrication, and cohesive properties to the drug(s) whichis being formulated into a dosage form.

Lubricants are typically added to avoid the material(s) being tabletedfrom sticking to the punches. Commonly used lubricants include magnesiumstearate and calcium stearate. Such lubricants are commonly included inthe final tableted product in amounts of less than 1% by weight.

In addition to lubricants, solid dosage forms often contain diluents.Diluents are frequently added in order to increase the bulk weight ofthe material to be tableted in order to make the tablet a practical sizefor compression. This is often necessary where the dose of the drug isrelatively small.

Another commonly used class of excipients in solid dosage forms arebinders. Binders are agents which impart cohesive qualities to thepowdered material(s). Commonly used binders include starch, and sugarssuch as sucrose, glucose, dextrose, and lactose.

Disintegrants are often included in order to ensure that the ultimatelyprepared compressed solid dosage form has an acceptable disintegrationrate in an environment of use (such as the gastrointestinal tract).Typical disintegrants include starch derivatives and salts ofcarboxymethyl cellulose.

There are three general methods of preparation of the materials to beincluded in the solid dosage form prior to compression: (1) drygranulation; (2) direct compression; and (3) wet granulation.

Dry granulation procedures may be utilized where one of theconstituents, either the drug or the diluent, has sufficient cohesiveproperties to be tableted. The method includes mixing the ingredients,slugging the ingredients, dry screening, lubricating and finallycompressing the ingredients.

In direct compression, the powdered material(s) to be included in thesolid dosage form is compressed directly without modifying the physicalnature of the material itself.

The wet granulation procedure includes mixing the powders to beincorporated into the dosage form in, e.g., a twin shell blender ordouble-cone blender and thereafter adding solutions of a binding agentto the mixed powders to obtain a granulation. Thereafter, the damp massis screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., viatray drying, the use of a fluid-bed dryer, spray-dryer, radio-frequencydryer, microwave, vacuum, or infra-red dryer.

The use of direct compression is limited to those situations where thedrug or active ingredient has a requisite crystalline structure andphysical characteristics required for formation of a pharmaceuticallyacceptable tablet. On the other hand, it is well known in the art toinclude one or more excipients which make the direct compression methodapplicable to drugs or active ingredients which do not possess therequisite physical properties. For solid dosage forms wherein the drugitself is to be administered in a relatively high dose (e.g., the drugitself comprises a substantial portion of the total tablet weight), itis necessary that the drug(s) itself have sufficient physicalcharacteristics (e.g., cohesiveness) for the ingredients to be directlycompressed.

Typically, however, excipients are added to the formulation which impartgood flow and compression characteristics to the material as a wholewhich is to be compressed. Such properties are typically imparted tothese excipients via a pre-processing step such as wet granulation,slugging, spray drying, spheronization, or crystallization. Usefuldirect compression excipients include processed forms of cellulose,sugars, and dicalcium phosphate dihydrate, among others.

A processed cellulose, microcrystalline cellulose, has been utilizedextensively in the pharmaceutical industry as a direct compressionvehicle for solid dosage forms. Microcrystalline cellulose iscommercially available under the tradename EMCOCEL® from Edward MendellCo., Inc. and as Avicel® from FMC Corp. Compared to other directlycompressible excipients, microcrystalline cellulose is generallyconsidered to exhibit superior compressibility and disintegrationproperties.

Another limitation of direct compression as a method of tabletmanufacture is the size of the tablet. If the amount of activeingredient is high, a pharmaceutical formulator may choose to wetgranulate the active with other excipients to attain an acceptably sizedtablet with the desired compact strength. Usually the amount offiller/binder or excipients needed in wet granulation is less than thatrequired for direct compression since the process of wet granulationcontributes to some extent toward the desired physical properties of atablet. Thus, despite the advantages of direct compression (such asreduced processing times and costs), wet granulation is widely used inthe industry in the preparation of solid dosage forms. Many of thoseskilled in the art prefer wet granulation as compared to directcompression because this method has a greater probability of overcomingany problems associated with the physical characteristics of the variousingredients in the formulation, thereby providing a material which hasthe requisite flow and cohesive characteristics necessary to obtain anacceptable solid dosage form.

The popularity of the wet granulation process as compared to the directcompression process is based on at least three advantages. First, wetgranulation provides the material to be compressed with better wettingproperties, particularly in the case of hydrophobic drug substances. Theaddition of a hydrophilic excipient makes the surface of a hydrophobicdrug more hydrophilic, easing disintegration and dissolution. Second,the content uniformity of the solid dosage forms is generally improved.Via the wet granulation method, all of the granules thereby obtainedshould contain approximately the same amount of drug. Thus, segregationof the different ingredients of the material to be compressed (due todifferent physical characteristics such as density) is avoided.Segregation is a potential problem with the direct compression method.Finally, the particle size and shape of the particles comprising thegranulate to be compressed are optimized via the wet granulationprocess. This is due to the fact that when a dry solid is wetgranulated, the binder “glues” particles together, so that theyagglomerate in the granules which are more or less spherical.

Due to the popularity of microcrystalline cellulose, pharmaceuticalformulators have deemed it desirable to include this excipient in aformulation which is wet granulated prior to tableting. Unfortunately,currently-available microcrystalline cellulose does not hold to thetypical principle that the amount of filler/binder needed in wetgranulation is less than that in direct compression. It is known thatthe exposure of the microcrystalline cellulose to moisture in the wetgranulation process severely reduces the compressibility of thisexcipient. The loss of compressibility of microcrystalline cellulose isparticularly problematic where the formulation dictates that the finalproduct will be relatively large in the environment of use. For example,if a pharmaceutical formulator desires to prepare a solid oral dosageform of a high dose drug, and the use of the wet granulation techniqueis deemed necessary, the loss of compressibility of the microcrystallinecellulose dictates that a larger amount of this material may be neededto obtain an acceptably compressed final product. The additional amountof microcrystalline cellulose needed adds cost to the preparation, butmore importantly adds bulk, making the product more difficult toswallow.

The loss of compressibility of microcrystalline cellulose when exposedto wet granulation has long been considered a problem in the art forwhich there has been no satisfactory solution.

Attempts have been made to provide an excipient having highcompressibility, a small bulk (high apparent density), and goodflowability, while being capable of providing satisfactorydisintegration of the solid dosage form, which is applicable to wetgranulation as well as to dry granulation and direct compression methodsfor preparation of solid dosage forms.

For example, U.S. Pat. No. 4,159,345 (Takeo, et al.) describes anexcipient which consists essentially of a microcrystalline cellulosehaving an average degree of polymerization of 60 to 375 and obtainedthrough acid hydrolysis or alkaline oxidative degradation of acellulosic substance selected from linters, pulps and regeneratedfibers. The microcrystalline cellulose is said to be a white cellulosicpowder having an apparent specific volume of 1.6-3.1 cc/g, a reposeangle of 35 to 42, a 200-mesh sieve residue of 2 to 80% by weight and atapping apparent specific volume of at least 1.4 cc/g.

In U.S. Pat. No. 4,744,987 (Mehra, et al.), a particulate co-processedmicrocrystalline cellulose and calcium carbonate composition isdescribed wherein the respective components are present in a weightratio of 75:25 to 35:65. The co-processed composition is said to beprepared by forming a well-dispersed aqueous slurry of microcrystallinecellulose and calcium carbonate and then drying the slurry to yield aparticulate product. The combination of these two ingredients is said toprovide a lower cost excipient which has tableting characteristicssimilar to those of microcrystalline cellulose and which would satisfy aneed for an economical excipient with good performance that is desiredby the vitamin market.

European Patent Application EP 0609976A1 (assigned to Asahi KaseiKabushiki Kaisha) describes an excipient comprising white powderymicrocrystalline cellulose having an average degree of polymerization offrom 100 to 375, preferably from 190 to 210, and an acetic acid holdingcapacity of 280% or more, preferably from 290 to 370%. The excipient issaid to exhibit high compactability and a high rate of disintegrationand is said to be obtained by heat-treating an aqueous dispersion ofpurified cellulose particles, which has a solids content of 40% or lessby weight, at 100 C or more, followed by drying, or by subjecting anaqueous dispersion of purified cellulose particles having a solidscontent of 23% or less by weight to thin film-forming treatment anddrying the resultant thin film. The excipient is said to possess a highcompressibility, and a good balance of compactability and rate ofdisintegration.

There still remains a need in the industry for a pharmaceuticalexcipient which possesses excellent compressibility whether utilized ina direct compression or wet granulation procedure.

DETAILED DESCRIPTION OF THE INVENTION

Excipients of the present invention comprise Microcrystalline Cellulose(MCC) and augmenting agents. Microcrystalline cellulose is a well-knowntablet diluent, binder and disintegrant. Its chief advantage over otherexcipients is that it can be directly compressed into self-bindingtablets which disintegrate rapidly when placed into water. Thiswidely-used ingredient is prepared by partially depolymerizing celluloseobtained as a pulp from fibrous plant material with dilute mineral acidsolutions. Following hydrolysis, the hydrocellulose thereby obtained ispurified via filtration and an aqueous slurry is spray dried to formdry, white odorless, tasteless crystalline powder of porous particles ofvarious sizes. Another method of preparing microcrystalline cellulose isdisclosed in U.S. Pat. No. 3,141,875. This reference disclosessubjecting cellulose to the hydrolytic action of hydrochloric acid atboiling temperatures so that amorphous cellulosic material can beremoved and aggregates of crystalline cellulose are formed. Theaggregates are collected by filtration, washed with water and aqueousammonia and disintegrated into small fragments, often called cellulosecrystallites by vigorous mechanical means such as a blender.Microcrystalline cellulose is commercially available in several gradeswhich range in average particle size from 20 to 200 microns.

Microcrystalline cellulose is water-insoluble, but the material has theability to draw fluid into a tablet by capillary action. The tabletsthen swell on contact and the microcrystalline cellulose thus acts as adisintegrating agent. The material has sufficient self-lubricatingqualities so as to allow a lower level of lubricant as compared to otherexcipients.

Typically, microcrystalline cellulose has an apparent density of about0.28 g/cm³ and a tap density of about 0.43 g/cm³ . Handbook ofPharmaceutical Excipients, pages 53-55.

When utilized in pharmaceutical applications, microcrystalline celluloseis typically used as a tablet binder/diluent in wet granulation anddirect compression formulations in amounts of 3-30% of the formulation,or more. However, it is known to use more or less microcrystallinecellulose in pharmaceutical products, depending upon the requirements ofthe formulation.

The novel excipients of the present invention also include one or morecompressibility augmenting agents. The compressibility augmentingagent(s) is present in amounts ranging from about 0.1% to about 50% byweight of microcrystalline cellulose.

Direct compression tablet manufacturing is preferred for many productsin the pharmaceutical industry. It is a simple process involving lessextensive equipment, operating time and cost. Microcrystalline celluloseis a good excipient for direct compression processing. Microcrystallinecellulose has inherently high compactibility due to its plasticdeformation and limited elastic recovery. Microcrystalline celluloseusually provides for good drug dispersion, even ordered mixing with somedrugs and particular grades of microcrystalline cellulose. However, thematerial flow properties are relatively poor for most grades ofmicrocrystalline cellulose. Intermittent and non-uniform flow can occuras the formulation moves from the hopper to the die on a tablet press.This non-uniform flow can lead to drug content variations in thefinished tableted dosage form.

The popularity of the wet granulation process as compared to the directcompression process is based on at least three potential advantages.First, wet granulation may provide the material to be compacted with amore hydrophilic nature, in order to improve the wetting, disintegrationand dissolution characteristics of some hydrophobic drugs oringredients. Second, the content uniformity and drugsegregation-resistance can be enhanced using a granulation step to lockdrug and excipient components together during blending. Finally, themicro metric characteristics of the component powders can be optimizedprior to compaction, which is often aided by incorporation of apolymeric binder. It is normally considered that this last propertyimbued by wet granulation will yield a significantly more compactibleproduct and consequently stronger, more robust tablets. However, it hasbeen found that the most compactable tableting excipient,microcrystalline cellulose, can lose between 30 and 50% of its tabletstrength enhancing characteristics, following wet granulation.Microcrystalline cellulose tablet weakening caused by wet granulation isobserved in all cases where water is added, although the magnitude ofloss of compactibility is directed related to the concentration of waterused, as well as granulation and drying energetics. This loss ofcompactibility can result in a very significant loss of functionality,generally leading to a requirement for a larger binder concentration inthe formulation and consequently less efficient and more costly tabletproduction as well as larger tablets.

We have found that the reduction in compactibility of microcrystallinecellulose which has been wet granulated is generally accompanied by adecrease in particle porosity, specific surface area available to adsorbnitrogen and also an increase in granule bulk density and friability.However, granule particle size distribution was found to have arelatively minor effect on granule compactibility. Wet granulation hasbeen found to have only a minor effect on the solubility parameters ofmicrocrystalline cellulose. Further, wet granulation does not alter theX-ray diffraction pattern and the Raman and 13C-NMR spectra ofmicrocrystalline cellulose. However, as a result of granulation, theinfrared spectra of microcrystalline cellulose obtained using thetechniques of attenuated total reflectance (ATRIR) and optical IRspectroscopy were altered slightly. This is hypothesized to indicatethat only the near-surface molecular layers may be significantlyinvolved in interactions with water. Granule properties, includingcompactibility, have also been found to be influenced by the amount ofgranulating fluid employed, the duration and rate of wet mass agitation,wet mass storage time before drying, and granule drying technique.Further, granule dewatering by solvent exchange was found to have abeneficial effect on granule compactibility.

It is hypothesized that the granulation-reduced microcrystallinecellulose compactibility is caused at least in significant part byincreasing intraparticle and/or interparticle hydrogen bonding. Forpurposes of the present invention, this phenomenon is termed“quasi-hornification” since, unlike hornification of cellulose fibersdescribed in the literature elsewhere, quasi-hornification ofmicrocrystalline cellulose has not ben observed by us to reduce theability of microcrystalline cellulose to absorb water vapor.Furthermore, quasi-hornified microcrystalline cellulose was found to befully reversible, unlike the hornification which occurs when celluloseis wetted. Microcalorimetry indicates that during adsorption of watervapor by granulated microcrystalline cellulose, the extent ofintraparticle bond disruption is greater than occurring during watervapor adsorption by ungranulated microcrystalline cellulose. Thisprovides evidence to support the theory that granulation results inincreased intraparticle hydrogen bonding, some of which is reversible onadsorption of water vapor.

The present invention is directed in part to a novel agglomeratedmicrocrystalline cellulose excipient which comprises a combination ofmicrocrystalline cellulose as described above together in intimateassociation with a compressibility augmenting agent. The novelagglomerated microcrystalline cellulose excipient is prepared in amanner which significantly reduces the hydrogen bonding between inter-and/or intra-molecular cellulose-to-cellulose bonding which occurs whenregular, commercial grade microcrystalline cellulose is exposed tomoisture (water). This can be accomplished, e.g., by preparing anaqueous slurry of microcrystalline cellulose, compressibility augmentingagent(s), and other optional ingredients, and drying the mixture in amanner which inhibits quasi-hornification.

The novel agglomerated microcrystalline cellulose excipient utilizes acompressibility augmenting agent which

(i) physically restricts the proximity of the interface between adjacentcellulose surfaces;

(ii) inhibits interactions between adjacent cellulose surfaces, forexample, via the creation of a hydrophobic boundary at cellulosesurfaces; or

(iii) accomplishes both (i) and (ii) above.

In one preferred embodiment of the invention, the compressibilityaugmenting agent which provides a physical barrier between adjacentcellulose surfaces is a silicon dioxide. Silicon dioxide is obtained byinsolubilizing dissolved silica in sodium silicate solution. Whenobtained by the addition of sodium silicate to a mineral acid, theproduct is termed silica gel. When obtained by the destabilization of asolution of sodium silicate in such a manner as to yield very fineparticles, the product is termed precipitated silica. Silicon dioxide isinsoluble in water. Prior to the present invention, silicon dioxide, andin particular colloidal silicon dioxide, was used mainly as a glidantand anti-adherent in tableting processes and encapsulation, promotingthe flowability of the granulation. The amount of silicon dioxideincluded in such tablets for those applications is very limited,0.1-0.5% by weight. Handbook of Pharmaceutical Excipients, ©1986American Pharmaceutical Association, page 255. This is due in part tothe fact that increasing the amount of silicon dioxide in the mixture tobe tableted causes the mixture to flow too well, causing a phenomenaknown to those skilled in the tableting art as “flooding”. If themixture flows too well, a varying tablet weight with uneven contentuniformity can result.

Those skilled in the art will appreciate that the name and/or method ofpreparation of the silicon dioxide utilized in the present invention isnot determinative of the usefulness of the product. Rather, aspreviously mentioned, it has been surprisingly discovered that it is thephysical characteristics of the silicon dioxide that are critical. Inparticular, it has been discovered that silicon dioxide having arelatively large particle size (and correspondingly small surface area),such as silica gel, is not useful in the preparation of the improvedmicrocrystalline cellulose products of the invention. The appendedclaims are deemed to encompass all forms of silicon dioxide having anaverage primary particle size from about 1 nm to about 100 μm, and/or asurface area from about 10 m²/g to about 500 m²/g.

The silicon dioxide utilized in the invention is of the very fineparticle size variety. In the more preferred embodiments of theinvention, the silicon dioxide utilized is a colloidal silicon dioxide.Colloidal silicon dioxide is a submicron fumed silica prepared by thevapor-phase hydrolysis (e.g., at 1110° C.) of a silicon compound, suchas silicon tetrachloride. The product itself is a submicron, fluffy,light, loose, bluish-white, odorless and tasteless amorphous powderwhich is commercially available from a number of sources, includingCabot Corporation (under the tradename Cab-O-Sil); Degussa, Inc. (underthe tradename Aerosil); E.I. DuPont & Co.; and W. R. Grace & Co.Colloidal silicon dioxide is also known as colloidal silica, fumedsilica, light anhydrous silicic acid, silicic anhydride, and silicondioxide fumed, among others. A variety of commercial grades of colloidalsilicon dioxide are produced by varying the manufacturing process. Thesemodifications do not affect the silica content, specific gravity,refractive index, color or amorphous form. However, these modificationsare known to change the particle size, surface areas, and bulk densitiesof the colloidal silicon dioxide products.

The surface area of the preferred class of silicon dioxides utilized inthe invention ranges from about 50 m²/gm to about 500 m²/gm. The averageprimary particle diameter of the preferred class of silicon dioxidesutilized in the invention ranges from about 5 nm to about 50 nm.However, in commercial colloidal silicon dioxide products, theseparticles are agglomerated or aggregated to varying extents. The bulkdensity of the preferred class of silicon dioxides utilized in theinvention ranges from about 20 g/l to about 100 g/l.

Commercially available colloidal silicon dioxide products have, forexample, a BET surface area ranging from about 50±15 m²/gm (AerosilOX50) to about 400±20 (Cab-O-Sil S17) or 390±40 m²/gm (Cab-O-Sil EH-5).Commercially available particle sizes range from a nominal particlediameter of 7 nm (e.g., Cab-O-Sil S-17 or Cab-O-Sil EH-5) to an averageprimary particle size of 40 nm (Aerosil OX50). The density of theseproducts range from 72.0±8 g/l (Cab-O-Sil S-17) to 36.8 g/l (e.g.,Cab-O-Sil M-5). The pH of the these products at 4% aqueous dispersionranges from pH 3.5-4.5. These commercially available products aredescribed for exemplification purposes of acceptable properties of thepreferred class of silicon dioxides only, and this description is notmeant to limit the scope of the invention in any manner whatsoever.

When the novel excipient of the invention utilizes a colloidal silicondioxide, it has been found that the resultant excipient productsurprisingly provides a compressibility which is substantially improvedin preferred embodiments even in comparison to the compressibility ofnormal “off-the-shelf” commercially available microcrystalline celluloseused in direct compression techniques.

In other embodiments of the present invention, it has been discoveredthat the compressibility of microcrystalline cellulose which is wetgranulated is significantly improved by a wider range of silicon dioxideproducts. Thus, in embodiments of the present invention where animprovement in overall compressibility of the microcrystalline cellulose(whether utilized in wet granulation or dry granulation) is notimportant, and the microcrystalline cellulose product is to be subjectedto wet granulation, it has been discovered that the surface area of thesilicon dioxide can be as low as about 50 m²/gm and the average primaryparticle diameter can be as large as about 100 μm. Such silicon dioxideproducts are also deemed to be encompassed within the scope of theinvention.

The coprocessed product consists of microcrystalline cellulose andsilicon dioxide in intimate association with each other. Magnificationsof the resultant particles indicate that the silicon dioxide isintegrated with, or partially coats, the surfaces of themicrocrystalline cellulose particles. When the amount of silicon dioxideincluded in the excipient is greater than about 20% by weight relativeto the microcrystalline cellulose, the silicon dioxide appears tosubstantially coat the surfaces of the microcrystalline celluloseparticles. The exact relationship of the two ingredients of theexcipients after coprocessing is not presently understood; however, forpurposes of description the coprocessed particles are described hereinas including an agglomerate of microcrystalline cellulose and silicondioxide in intimate association with each other. The coprocessedparticles are not necessarily uniform or homogeneous. Rather, undermagnification, e.g., scanning electron microscope at 500×, the silicondioxide at the preferred percent inclusion appears to be an“edge-coating”.

Depending upon the amount and type of drying, the concentration of themicrocrystalline cellulose and silicon dioxide in the suspension, thenovel compressible particles will have different particle sizes,densities, pH, moisture content, etc.

The particulate coprocessed product of this aspect of the presentinvention possesses desirable performance attributes that are notpresent when the combination of microcrystalline cellulose and silicondioxide are combined as a dry mixture. It is believed that thebeneficial result obtained by the combination of these two materials isdue to the fact that the two materials are intimately associated witheach other.

One skilled in the art will appreciate that other classes of compoundshaving size, surface area, and other similar physical characteristics tosilicon dioxide may be useful in physically forming a barrier which mayreduce the surface-to-surface interactions (including hydrogenbonding)between cellulose surfaces. Such materials include (but are not limitedto) non-silicon metal oxides. Such obvious modifications of the presentinvention are deemed to be within the contemplated scope of the appendedclaims.

In other preferred embodiments of the invention, the compressibilityaugmenting agent is a material which inhibits interactions betweenadjacent cellulose surfaces, for example, via the creation of ahydrophobic boundary or barrier at cellulose surfaces. As previouslymentioned, compressibility augmenting agents which inhibitsurface-to-surface interactions between surfaces of the microcrystallinecellulose include any material which has the ability, via a portion ofthe molecule, to bind or interact with the surface of themicrocrystalline cellulose and at the same time, via another portion ofthe molecule, to inhibit the attraction of the cellulose surfaces, e.g.,via a hydrophobic portion or “tail”. Suitable compressibility augmentingagents will have an HLB value of at least 10, preferably at least about15, and more preferably from about 15 to about 40 or greater.Compressibility augmenting agents having an HLB value from about 30 toabout 40 or greater is most preferred.

Surfactants which may be used in the present invention as acompressibility augmenting agent generally include allpharmaceutically-acceptable surfactants, with the proviso that thesurfactant have an HLB value of at least 10, and preferably at leastabout 15.

In certain preferred embodiments, the HLB value of the surfactant isfrom about 15 to 50, and in further embodiments is most preferably fromabout 15.6 to about 40. Suitable pharmaceutically-acceptable anionicsurfactants include, for example, those containing carboxylate,sulfonate, and sulfate ions. Those containing carboxylate ions aresometimes referred to as soaps and are generally prepared bysaponification of natural fatty acid glycerides in alkaline solutions.The most common cations associated with these surfactants are sodium,potassium, ammonium and triethanolamine. The chain length of the fattyacids range from 12 to 18. Although a large number of alkyl sulfates areavailable as surfactants, one particularly preferred surfactant issodium lauryl sulfate, which has an HLB value of about 40.

In the pharmaceutical arts, sodium lauryl sulfate has been used as anemulsifying agent in amounts of up to about 0.1% by weight of theformulation. However, surfactants such as sodium lauryl sulfate havebeen included in coprocessed microcrystalline cellulose compositions.Moreover, surfactants have been used in the amounts described herein toimprove the compressibility of microcrystalline cellulose especially inwet granulations. Sodium lauryl sulfate is a water-soluble salt,produced as a white or cream powder, crystals, or flakes and is used asa wetting agent and detergent. Also known as dodecyl sodium sulfate,sodium lauryl sulfate is actually a mixture of sodium alkyl sulfatesconsisting chiefly of sodium lauryl sulfate. Sodium lauryl sulfate isalso known as sulfuric acid monododecyl ester sodium salt. Furthermore,sodium lauryl sulfate is readily available from commercial sources suchas Sigma or Aldrich in both solid form and as a solution. The solubilityof sodium lauryl sulfate is about 1 gm per 10 ml/water. The fatty acidsof coconut oil, consisting chiefly of lauric acid, are catalyticallyhydrogenated to form the corresponding alcohols. The alcohols are thenesterified with sulfuric acid (sulfated) and the resulting mixture ofalkyl bisulfates (alkyl sulfuric acids) is converted into sodium saltsby reacting with alkali under controlled conditions of pH.

Alternative anionic surfactants include docusate salts such as thesodium salt thereof. Other suitable anionic surfactants include, withoutlimitation, alkyl carboxylates, acyl lactylates, alkyl ethercarboxylates, N-acyl sarcosinates, polyvalent alkyl carbonates, N-acylglutamates, fatty acid, polypeptide condensates and sulfuric acidesters.

In other aspects of the invention amphoteric (amphipathic/amphiphilicsurfactants), nonionic surfactants and/or cationic surfactants areincluded in the coprocessed compositions of the invention. Suitablepharmaceutically-acceptable non-ionic surfactants such as, for example,polyoxyethylene compounds, lecithin, ethoxylated alcohols, ethoxylatedesters, ethoxylated amides, polyoxypropylene compounds, propoxylatedalcohols, ethoxylated/propoxylated block polymers, propoxylated esters,alkanolamides, amine oxides, fatty acid esters of polyhydric alcohols,ethylene glycol esters, diethylene glycol esters, propylene glycolesters, glycerol esters, polyglycerol fatty acid esters, SPAN's (e.g.,sorbitan esters), TWEEN's (i.e., sucrose esters), glucose (dextrose)esters and simethicone. The HLB for one acceptable non-ionic surfactant,polysorbate 40, is about 15.6.

Other suitable pharmaceutically-acceptable surfactants include acacia,benzalkonium chloride, cholesterol, emulsifying wax, glycerolmonostearate, lanolin alcohols, lecithin, poloxamer, polyoxyethylene,and castor oil derivatives.

Those skilled in the art will further appreciate that the name and/ormethod of preparation of the surfactant utilized in the presentinvention is not determinative of the usefulness of the product. Rather,as previously mentioned, it has been surprisingly discovered that it isthe physical characteristics of surfactants, especially those of theanionic class such as sodium lauryl sulfate, which are critical. Inparticular, it has been discovered that when an anionic surfactant suchas sodium lauryl sulfate is coprocessed with microcrystalline cellulosein the amounts described herein, improved microcrystalline celluloseproducts of the invention result.

When the novel excipient of the invention utilizes an anionicsurfactant, it has been found that the resultant excipient productsurprisingly provides a compressibility which is substantially improvedin preferred embodiments even in comparison to the compressibility ofnormal “off-the-shelf” commercially available microcrystalline celluloseused in direct compression techniques. In other embodiments of thepresent invention, it has been discovered that the compressibility ofmicrocrystalline cellulose which is wet granulated is significantlyimproved by coprocessing the microcrystalline cellulose with an anionicsurfactant such as sodium lauryl sulfate.

Since microcrystalline cellulose is substantially water insoluble, theparticle size of this ingredient in the well-dispersed aqueous slurry isdirectly related to its particle size as it was introduced into theaqueous solution. Most surfactants, on the other hand, tend to be watersoluble. Sodium lauryl sulfate, for example, is relatively soluble inwater (1 g/10ml) and, therefore, dissolves in the aqueous slurry. Itshould be understood, however, that the coprocessed products of thepresent invention are not solely limited to those which contain adissolved surfactant. The contemplated compositions can also be preparedfrom slurries which contain a dispersion of the surfactant as well asthe microcrystalline cellulose.

Highly polar molecules having the requisite HLB value range set forthabove may also be utilized as the compressibility augmenting agent. Suchhighly polar molecules include certain dyes, particular those which maybe capable of binding to the cellulose surface while thereafter creatinga relatively hydrophobic environment due to the presence of ahydrophobic portion of the molecule (e.g., a hydrophobic tail) which“points away” from the cellulose surface and discourages hydrophilicsurface-to-surface cellulose interactions, such as hydrogen-bonding.Preferably, the dye is one which is pharmaceutically acceptable forinclusion in solid dosage forms.

Examples of suitable dyes include Congo Red (chemical name:3,3′-[[1,1′Biphenyl]-4,4′diylbis-(azo)]bis[4-amino-1-naphthalenesulfonicacid] disodium salt; FD&C Red No. 40 (also known as “Allura Red”)(chemical name: Disodium salt of 6-hydroxy-5[(2-methyl-4-sulfophenyl)azo]-2-naphthalenesulfonic acid); FD&C Yellow No. 5 (common name:tartrazine) (chemical name:5-oxo-1-(p-sulfophenyl)-4-[(p-sulfophenyl)azo]-2-pyrazoline-3-carboxylicacid, trisodium salt); FD&C Yellow No. 6 (common name: Sunset YellowFCF) (chemical name: Disodium salt of1-p-sulphophenylazo-2-naphthol-6-sulfonic acid); Ponceau 4R (chemicalname: Trisodium-2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-6,8-disulfonate); Brown HT (chemical name: Disodium4,4′-(2,4-dihydroxy-5-hydroxymethyl-3, 3-phenylenebisazo)di(napthalene-1-sulfonate)); Brilliant Black BN (Chemical name:Tetrasodium4-acetamido-5-hyroxy-6-[7-sulfonato-4-(4-sulfonatophenylazo)-1-naphthylazo]naphthalene-1,7-disulfonate);Carmoisine (chemical name: Disodium4-hydroxy-3-(4-sulfanato-1-naphythylazo) Naphthalene-1-sulfonate);Amaranth (chemical name: Trisodium2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-3, 6-disulfonate);and mixtures thereof.

Other highly polar molecules having the requisite HLB value range setforth above which may be utilized as the compressibility augmentingagent include the active agents themselves. For example, it iswell-known to those skilled in the art that certain classes ofpharmaceuticals, such as anti-pyschotic drugs, are highly polar innature and may be utilized as a compressibility augmenting agent inaccordance with this invention.

One skilled in the art will appreciate that other classes of highlypolar compounds may be useful in reducing the surface-to-surfaceinteractions (including hydrogen-bonding) between cellulose surfaces.Such obvious modifications of the present invention are deemed to bewithin the contemplated scope of the appended claims.

It is preferred in the present invention that the microcrystallinecellulose and compressibility augmenting agent are coprocessed,resulting in an intimate association of these ingredients, rather thanbeing combined, e.g., as a dry mixture. In preferred embodiments of thepresent invention, an aqueous slurry of the microcrystalline cellulose,the compressibility augmenting agent(s) and other optional ingredientsis prepared in order to obtain (after a drying step) agglomeratedparticles wherein these components are intimately associated. Theaqueous slurry of the microcrystalline cellulose and compressibilityaugmenting agent are introduced into the spray dryer as a single aqueousmedium. However, it is possible to separately introduce each ingredientinto separate aqueous medium which are then combined. Other proceduresfor combining these materials with or without other optional ingredientsknown to those skilled in the art are deemed to be equivalent to thespray-drying technique described above, and are further deemed to beencompassed by the appended claims.

In preferred embodiments of the present invention, the coprocessing ofthe microcrystalline cellulose and compressibility augmenting agent isaccomplished by forming a well-dispersed aqueous slurry ofmicrocrystalline cellulose in which the compressibility augmenting agenthas been dissolved, and thereafter drying the slurry and forming aplurality of microcrystalline cellulose-based excipient particles.Typically, microcrystalline cellulose is first added to an aqueoussolution so that a slurry or suspension containing from about 0.5% toabout 25% microcrystalline cellulose in the form of solids is obtained.Preferably, the slurry or suspension contains from about 15% to 20%microcrystalline cellulose and most preferably from about 17% to about19% microcrystalline cellulose. At this stage, it is optionallydesirable to adjust the pH of the slurry to about neutral with ammoniumhydroxide, sodium hydroxide, and mixtures thereof or the like. Thesuspension is kept under constant agitation for a sufficient time toassure a uniform distribution of the solids prior to being combined withthe compressibility augmenting agent.

For example, silicon dioxide is added to the suspension or slurry inamounts ranging from 0.1% to about 20% by weight, based on the amount ofmicrocrystalline cellulose, amounts from about 0.5% to about 10% arepreferred while amounts of from about 1.25% to about 5% by weight areespecially preferred. There is no appreciable dissolution of eitheringredient (microcrystalline cellulose or silicon dioxide), since bothare relatively water insoluble. The microcrystalline cellulose andsilicon dioxide are well-dispersed in the slurry or suspension prior todrying and forming the novel particles.

On the other hand, the surfactant is added to the suspension or slurryin amounts ranging from about 0.1% to about 20% by weight, preferablyfrom about 0.1 to about 5% by weight, based on the amount ofmicrocrystalline cellulose, and in certain embodiments preferably fromabout 0.15% to about 0.4%, by weight. When the surfactant is sodiumlauryl sulfate, the amount is most preferably from about 0.2 to about0.3%, by weight. The surfactant can be added to the suspension as eithera solid or in solution form. The microcrystalline cellulose is thuswell-dispersed in the slurry or suspension and the surfactant isdissolved therein prior drying and forming the novel particles. It willbe understood that other useful surfactants can be used in like amountsor even greater amounts, i.e. up to 20% by weight or even more. Theusable concentration range for the selected surfactant depends in partupon not only its molecular weight but also its degree of foaming,particularly when present in agitated slurries which will be spray driedto form the desired particulate. Thus, in those aspects of the inventionwhere surfactants other than sodium lauryl sulfate are coprocessed withthe microcrystalline cellulose, it is to be understood that thesurfactant will be present in an amount which enhances thecompressibility of the Microcrystalline cellulose and yet does not havea degree of foaming which would substantially inhibit spray drying.

Other compressibility augmenting agents (including highly polar dyes,highly polar drugs, and other useful materials having a HLB from about15 to about 50) may be included in the aqueous slurry in amounts rangingfrom about 0.1% to about 20%, by weight, and more preferably from about0.5 to about 10%, by weight.

After a uniform mixture of the ingredients is obtained in thesuspension, the suspension is dried to provide a plurality ofmicrocrystalline cellulose-based excipient particles having enhancedcompressibility (e.g., dried in a manner which inhibitsquasi-hornification).

In the (preferred) spray-drying process, the aqueous dispersion ofmicrocrystalline cellulose and surfactant is brought together with asufficient volume of hot air to produce evaporation and drying of theliquid droplets. The highly dispersed slurry of microcrystallinecellulose and surfactant is pumpable and capable of being atomized. Itis sprayed into a current of warm filtered air, which supplies the heatfor evaporation and conveys a dried product to a collecting device. Theair is then exhausted with the removed moisture. The resultantspray-dried powder particles are approximately spherical in shape andare relatively uniform in size, thereby possessing excellentflowability. The coprocessed product consists of microcrystallinecellulose and surfactant in intimate association with each other. Theexact relationship of the two ingredients of the excipients aftercoprocessing is not presently understood; however, for purposes ofdescription the coprocessed particles are described herein as includingan agglomerate of microcrystalline cellulose and surfactant in intimateassociation with each other. By “intimate associate”, it is meant thatthe surfactant has in some manner been integrated with themicrocrystalline cellulose particles, e.g., via a partial coating of themicrocrystalline particles, as opposed to a chemical interaction of thetwo ingredients. The term “intimate association” is therefore deemed forpurposes of the present description as being synonymous with“integrated” or “united”. The coprocessed particles are not necessarilyuniform or homogeneous.

It is preferred that the suspension be dried using spray-dryingtechniques, as they are known in the art. Other drying techniques,however, such as flash drying, ring drying, micron drying, tray drying,vacuum drying, radio-frequency drying, and possibly microwave drying,may also be used, although spray drying is preferred.

Depending upon the amount and type of drying, the concentration of themicrocrystalline cellulose and compressibility augmenting agent in thesuspension, the novel compressible particles will have differentparticle sizes, densities, pH, moisture content, etc.

The particulate coprocessed product of the present invention possessesdesirable performance attributes that are not present when thecombination of microcrystalline cellulose and compressibility augmentingagent are combined as a dry mixture. It is believed that the beneficialresult obtained by the combination of these two materials is due to thefact that the two materials are intimately associated with each other.It has also been found that intimate association of Microcrystallinecellulose and other detergent-like materials such as simethicone, evenwhen they are dissolved/dispersed in the aqueous solutions which formthe Microcrystalline cellulose slurry, fail to provide Microcrystallinecellulose with enhanced compressibility.

The average particle size of the agglomerated microcrystalline celluloseexcipient of the present invention ranges from about 10 microns to about1000 microns. Particle sizes of about 10-500 microns are preferred,particle sizes of about 30-250 microns are more preferred and particlesizes of about 40-200 microns are most preferred. It will be appreciatedby those of ordinary skill in the art that the drying of the aqueoussuspension results in a random size distribution of the novel excipientparticles being produced. For example, if spray drying techniques areused, droplet size, temperatures, agitation, dispersion, air flow,atomizer wheel speed, etc. will effect final particle size. Furthermore,it is within the scope of the invention to sort or mechanically alterthe dried particles according to ranges of particle sizes depending uponend uses. The particle size of the integrated excipient is not narrowlycritical, the important parameter being that the average size of theparticle must permit the formation of a directly compressible excipientwhich forms pharmaceutically acceptable tablets.

The novel agglomerated microcrystalline cellulose excipient has a bulk(loose) density ranging from about 0.2 g/ml to about 0.6 g/ml, and mostpreferably from about 0.22 g/ml to about 0.55 g/ml. The novel excipienthas a tapped density ranging from about 0.20 g/ml to about 0.70 g/ml,and most preferably from about 0.35 g/ml to about 0.60 g/ml. The pH ofthe particles is most preferably about neutral, although granulateshaving a pH of from about 3.0 to about 8.5 are possible. The moisturecontent of the excipient particles will broadly range from about 0.5% toabout 15%, preferably from about 2.5% to about 6%, and most preferablyfrom about 3.0% to about 5% by weight.

The angle of repose is a measurement used to determine the flowcharacteristics of a powder. The angle of repose is subject toexperiment and experimenter, but in a comparative test, the novelexcipient is superior.

The novel agglomerated microcrystalline cellulose excipient of theinvention is free-flowing and directly compressible. Accordingly, theexcipient may be mixed in the desired proportion with an active agentand optional lubricant (dry granulation), and then directly compressedinto solid dosage forms. In preferred embodiments of the presentinvention wherein the surfactant is sodium lauryl sulfate, the novelexcipient represents an augmented microcrystalline cellulose havingimproved compressibility as compared to standard commercially availablegrades of microcrystalline cellulose.

Alternatively, all or part of the excipient may be subjected to a wetgranulation with the active ingredient. A representative wet granulationincludes loading the novel excipient particles into a suitablegranulator, such as those available from Baker-Perkins, and granulatingthe particles together with the active ingredient, preferably using anaqueous granulating liquid. The granulating liquid is added to themixture with stirring until the powdery mass has the consistency of dampsnow and then wet screened through a desired mesh screen, for example,having a mesh from about 12 to about 16. The screened granulate is thendried, using standard drying apparatus such as a convection oven beforeundergoing a final screening. Additional dry screening of this materialis possible, such as by using screens of from about 40 to about 200mesh. Those materials flowing through 40 and 60 mesh screens may befurther ground prior to ultimate tablet formulation. The thus obtainedgranulate containing the novel excipient is now capable of undergoingtableting or otherwise placed into a unit dosage form.

In certain preferred embodiments, a portion of the total amount of thenovel excipient is wet granulated with the active ingredient, andthereafter the additional portion of the novel excipient is added to thegranulate. In yet other embodiments, the additional portion of the novelexcipient to be added to the excipient/active ingredient granulate maybe substituted with conventional microcrystalline cellulose, or otherexcipients commonly used by those skilled in the art, depending ofcourse upon the requirements of the particular formulation.

By virtue of the novel excipient of the present invention, the amount ofthe novel excipient compared to the amount of microcrystalline cellulosewhich must be used in a wet granulation technique to obtain anacceptable solid dosage form is substantially reduced.

In other embodiments of the invention, a further material is added tothe aqueous slurry of microcrystalline cellulose and compressibilityaugmenting. Such additional materials include silicon dioxides,non-silicon metal oxides, starches, starch derivatives, surfactants,polyalkylene oxides, cellulose ethers, celluloses esters, mixturesthereof, and the like. Specific further materials which may be includedin the aqueous slurry (and consequently in the resultant agglomeratedmicrocrystalline cellulose excipient) are aluminum oxide, stearic acid,kaolin, polydimethylsiloxane, silica gel, titanium dioxide, diatomaceousearth, corn starch, high amylose corn starch, high amylopectin cornstarch, sodium starch glycolate, hydroxylated starch, modified potatostarch, mixtures thereof, and the like. These additives may be includedin desired amounts which will be apparent to those skilled in the art.

In addition to one or more active ingredients, additionalpharmaceutically acceptable excipients (in the case of pharmaceuticals)or other additives known to those skilled in the art (fornon-pharmaceutical applications) can be added to the novel excipientprior to preparation of the final product. For example, if desired, anygenerally accepted soluble or insoluble inert pharmaceutical filler(diluent) material can be included in the final product (e.g., a soliddosage form). Preferably, the inert pharmaceutical filler comprises amonosaccharide, a disaccharide, a polyhydric alcohol, inorganicphosphates, sulfates or carbonates, and/or mixtures thereof Examples ofsuitable inert pharmaceutical fillers include sucrose, dextrose,lactose, xylitol, fructose, sorbitol, calcium phosphate, calciumsulfate, calcium carbonate, “off-the-shelf” microcrystalline cellulose,mixtures thereof, and the like.

An effective amount of any generally accepted pharmaceutical lubricant,including the calcium or magnesium soaps may optionally be added to thenovel excipient at the time the medicament is added, or in any eventprior to compression into a solid dosage form. The lubricant maycomprise, for example, magnesium stearate in any amount of about 0.5-3%by weight of the solid dosage form. In embodiments where a surfactant isincluded as part or all of the compressibility augmenting agent, anadditional inclusion lubricant may not be necessary.

The complete mixture, in an amount sufficient to make a uniform batch oftablets, may then subjected to tableting in a conventional productionscale tableting machine at normal compression pressures for thatmachine, e.g., about 1500-10,000 lbs/sq in. The mixture should not becompressed to such a degree that there is subsequent difficulty in itshydration when exposed to gastric fluid.

The average tablet size for round tablets is preferably about 50 mg to500 mg and for capsule-shaped tablets about 200 mg to 2000 mg. However,other formulations prepared in accordance with the present invention maybe suitably shaped for other uses or locations, such as other bodycavities, e.g., periodontal pockets, surgical wounds, vaginally. It iscontemplated that for certain uses, e.g., antacid tablets, vaginaltablets and possibly implants, that the tablet will be larger.

The active agent(s) which may be incorporated with the novel excipientdescribed herein into solid dosage forms invention include systemicallyactive therapeutic agents, locally active therapeutic agents,disinfecting agents, chemical impregnants, cleansing agents, deodorants,fragrances, dyes, animal repellents, insect repellents, fertilizingagents, pesticides, herbicides, fungicides, and plant growth stimulants,and the like.

A wide variety of therapeutically active agents can be used inconjunction with the present invention. The therapeutically activeagents (e.g. pharmaceutical agents) which may be used in thecompositions of the present invention include both water soluble andwater insoluble drugs. Examples of such therapeutically active agentsinclude antihistamines (e.g., dimenhydrinate, diphenhydramine,chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g.,aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.),non-steroidal anti-inflammatory agents (e.g., naproxyn, diclofenac,indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide),anti-epileptics (e.g., phenytoin, meprobamate and nitrazepam),vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine),anti-tussive agents and expectorants (e.g., codeine phosphate),anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g.atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g.,ethacrynic acid, bendrofluazide), anti-hypotensives (e.g., propranolol,clonidine), antihypertensives (e.g., clonidine, methyldopa),bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone,triamcinolone, prednisone), antibiotics (e.g., tetracycline),antihemorrhoidals, hypnotics, psychotropics, antidiarrheals, mucolytics,sedatives, decongestants, laxatives, vitamins, stimulants (includingappetite suppressants such as phenylpropanolamine). The above list isnot meant to be exclusive.

A wide variety of locally active agents can be used in conjunction withthe novel excipient described herein, and include both water soluble andwater insoluble agents. The locally active agent(s) which may beincluded in the controlled release formulation of the present inventionis intended to exert its effect in the environment of use, e.g., theoral cavity, although in some instances the active agent may also havesystemic activity via absorption into the blood via the surroundingmucosa.

The locally active agent(s) include antifungal agents (e.g.,amphotericin B, clotrimazole, nystatin, ketoconazole, miconazol, etc.),antibiotic agents (penicillins, cephalosporins, erythro mycin,tetracycline, aminoglycosides, etc.), antiviral agents (e.g, acyclovir,idoxuridine, etc.), breath fresheners (e.g. chlorophyll), antitussiveagents (e.g., dextromethorphan hydrochloride), anti-cariogenic compounds(e.g., metallic salts of fluoride, sodium monofluorophosphate, stannousfluoride, amine fluorides), analgesic agents (e.g., methylsalicylate,salicylic acid, etc.), local anesthetics (e.g., benzocaine), oralantiseptics (e.g., chlorhexidine and salts thereof, hexylresorcinol,dequalinium chloride, cetylpyridinium chloride), anti-inflammatoryagents (e.g., dexamethasone, betamethasone, prednisone, prednisolone,triamcinolone, hydrocortisone, etc.), hormonal agents (oestriol),antiplaque agents (e.g, chlorhexidine and salts thereof, octenidine, andmixtures of thymol, menthol, methysalicylate, eucalyptol), acidityreducing agents (e.g., buffering agents such as potassium phosphatedibasic, calcium carbonate, sodium bicarbonate, sodium and potassiumhydroxide, etc.), and tooth desensitizers (e.g., potassium nitrate).This list is not meant to be exclusive. The solid formulations of theinvention may also include other locally active agents, such asflavorants and sweeteners. Generally any flavoring or food additive suchas those described in Chemicals Used in Food Processing, pub 1274 by theNational Academy of Sciences, pages 63-258 may be used. Generally, thefinal product may include from about 0.1% to about 5% by weightflavorant.

The tablets of the present invention may also contain effective amountsof coloring agents, (e.g., titanium dioxide, F. D. & C. and D. & C.dyes; see the Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 5,pp. 857-884, hereby incorporated by reference), stabilizers, binders,odor controlling agents, and preservatives.

Alternatively, the novel excipient can be utilized in other applicationswherein it is not compressed. For example, the granulate can be admixedwith an active ingredient and the mixture then filled into capsules. Thegranulate can further be molded into shapes other than those typicallyassociated with tablets. For example, the granulate together with activeingredient can be molded to “fit” into a particular area in anenvironment of use (e.g., an implant). All such uses would becontemplated by those skilled in the art and are deemed to beencompassed within the scope of the appended claims.

In further embodiments of the invention, more than one compressibilityaugmenting agent is used. Thus, for example, it is possible to use twoor more agents which act as physical barriers (e.g., physicallyrestricting the proximity of the interface between adjacent cellulosesurfaces); or to use two or more agents which inhibit interactionsbetween adjacent cellulose surfaces, for example, via the creation of ahydrophobic boundary at cellulose surfaces (e.g., surfactants having therequisite HLB value, and/or highly polar materials such as thepreviously mentioned dyes).

In certain preferred embodiments, two or more compressibility enhancingagents are used which provide an effect by different mechanisms, such asone agent which acts as a physical barrier (such as colloidal silicondioxide), and another agent which inhibit interactions between adjacentcellulose surfaces (for example, sodium lauryl sulfate). In suchembodiments, it is preferred that both agents are incorporated into theaqueous slurry and dried (e.g., via spray drying) to form agglomeratedparticles in which the microcrystalline cellulose, colloidal silicondioxide and sodium lauryl sulfate are in intimate association. Suchpreferred embodiments are capable of providing a synergisticallyimproved microcrystalline cellulose excipient which has propertiesdescribed above which are at least as good, and preferably improved, ascompared to t the properties of the novel microcrystalline celluloseexcipients which include only one class of these compressibilityaugmenting agents.

SUSTAINED-RELEASE CARRIER

Matrix formulations

In one embodiment of the invention, the sustained-release carrier isincorporated in a sustained-release matrix to impart sustained-releaseof the active agent from the final formulation. The sustained releasecarrier may be hydrophobic or hydrophilic. Suitable materials which maybe included in the sustained release carrier of the present inventioninclude alkylcelluloses such as natural or synthetic cellulosesderivatives (e.g. ethylcellulose), acrylic and methacrylic acid polymersand copolymers, zein, and mixtures thereof

In another embodiment, suitable biocompatible, preferably biodegradablepolymers can be utilized as the sustained release carrier. Thebiodegradable polymeric material may comprise a polylactide, apolyglycolide, a poly(lactide-co-glycolide), a polyanhydride, apolyorthoester, polycaprolactones, polyphosphazenes, polysaccharides,proteinaceous polymers, soluble derivatives of polysaccharides, solublederivatives of proteinaceous polymers, polypeptides, polyesters, andpolyorthoesters. The polysaccharides may be poly-1,4-glucans, e.g.,starch glycogen, amylose, amylopectin, and mixtures thereof Thebiodegradable hydrophilic or hydrophobic polymer may be a water-solublederivative of a poly-1,4-glucan, including hydrolyzed amylopectin,hydroxyalkyl derivatives of hydrolyzed amylopectin such as hydroxyethylstarch (HES), hydroxyethyl amylose, dialdehyde starch, and the like.

In yet other preferred embodiments, sustained-release of the activeagent is accomplished via a sustained release carrier comprising asynthetic or naturally occurring gum. Examples of naturally occurringgums include, e.g., the heteropolysaccharides and homopolysaccharides.An especially preferred heteropolysaccharide is xanthan gum, which is ahigh molecular weight (>10⁶) heteropolysaccharide. Other preferredheteropolysaccharides include derivatives of xanthan gum, such asdeacylated xanthan gum, the carboxymethyl ether, and the propyleneglycol ester.

The homopolysaccharides useful in the present invention includegalactomannan gums, which are polysaccharides composed solely of mannoseand galactose. Preferred galactomannan gums are those which are capableof cross-linking with the heteropolysaccharide. In particular,galactomannans which have higher proportions of unsubstituted mannoseregions have been found to achieve more interaction with theheteropolysaccharide when exposed to an environmental fluid. Locust beangum, which has a higher ratio of mannose to galactose, is especiallypreferred as compared to other galactomannans such as guar andhydroxypropyl guar.

Other natural or synthetic gums known to those skilled in the food andpharmaceutical arts are also useful as the controlled release carrier ofthe invention. Such gums include alginic acid derivatives, carageenan,tragacanth, acacia, karaya, guar gum, agar, acacia, galactans, mannans,and the like.

Water swellable polymers may be used in addition to or instead of gumsto promote sustained-release of the active agent from the finalformulation. Such water swellable polymers include cellulose ethers,carboxyvinyl polymer and the like.

The combination of xanthan gum with locust bean gum is an especiallypreferred gum combination. In certain embodiments, the controlledrelease properties of the sustained-release carrier are optimized whenthe ratio of heteropolysaccharide gum to galactomannan gum is from about3:1 to about 1:3, and most preferably about 1:1. However, in thisembodiment, the sustained release carrier of the invention may comprisefrom about 1% to about 99% by weight heteropolysaccharide gum and fromabout 99% to about 1% by weight homopolysaccharide gum.

Optionally, the sustained-release carrier includes a release modifyingagent. A release modifying agent according to the invention includes anypharmaceutically acceptable substance which my alter, e.g. prolong orincrease, the release rate of the active agent form the formulation uponexposure to an aqueous environment, e.g. gastric fluid or dissolutionmedium. Suitable release modifying agents which may be incorporated intothe matrix formulations of the present invention include, e.g.,monovalent or multivalent metal cations. Preferably, the salts areinorganic salts, including e.g., alkali metal and/or alkaline earthmetal sulfates, chlorides, borates, bromides, citrates, acetates,lactates, etc. In particular, these salts include, e.g., calciumsulfate, sodium chloride, potassium sulfate, sodium carbonate, lithiumchloride, tripotassium phosphate, sodium borate, potassium bromide,potassium fluoride, sodium bicarbonate, calcium chloride, magnesiumchloride, sodium citrate, sodium acetate, calcium lactate, magnesiumsulfate and sodium fluoride. Multivalent metal cations may also beutilized. In preferred embodiments, the release modifying agents arebivalent. Particularly preferred salts are calcium sulfate and sodiumchloride.

In those embodiments including a release modifying agent any effectiveamount may be employed. Preferably, the release modifying agent isincluded in an amount ranging from about 1 to about 20% by weight of asustained-release carrier comprising xanthan gum and locust bean gum.

Other release modifying agents include sugars, e.g. sucrose, starches,water-soluble alkylcellulose derivatives such ashydroxypropylmethylcellulose, urea, and the like.

Mixtures of any of the foregoing, and other pharmaceutically acceptablerelease retardants or release modifying agents known to those skilled inthe art may also be used in accordance with the present invention.

The final sustained-release oral dosage form may contain from about 1 toabout 99% (by weight) of sustained release carrier. Preferably, theweight percent of the sustained release carrier ranges from about 1 toabout 80%.

In certain preferred embodiments of the present invention, the sustainedrelease carrier is a pharmaceutically acceptable acrylic polymer,including but not limited to acrylic acid and methacrylic acidcopolymers, methyl methacrylate, methyl methacrylate copolymers,ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamine copolymer, poly(methyl methacrylate),poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.In other embodiments, the sustained-release carrier may further includea relatively hydrophilic material, including but not limited tomaterials such as hydroxyalkylcelluloses such ashydroxypropylmethylcellulose and mixtures of the foregoing.

A pharmaceutically acceptable plasticizer may also optionally beincluded in the sustained-release carrier of the present invention. Anon-limiting list of plasticizers includes include water insolubleplasticizers such as dibutyl sebacate, diethyl phthalate, triethylcitrate, tributyl citrate, and triacetin, although it is possible thatother water-insoluble plasticizers (such as acetylated monoglycerides,phthalate esters, castor oil, etc.) may be used. Triethyl citrate is anespecially preferred plasticizer.

In addition to the above ingredients, a sustained-release carrier mayalso include suitable quantities of pharmaceutical adjuvants, e.g.,diluents, lubricants, binders, granulating aids, colorants, flavorantsand glidants that are conventional in the pharmaceutical art. Anon-limiting list of suitable adjuvants include spray dried lactose,polyvinylpyrrolidone (PVP), talc, magnesium stearate, and mixturesthereof The quantities of these additional materials will be sufficientto provide the desired effect to the desired formulation. The finalformulation may contain up to about 50% by weight of the final dosageform, if desired.

Other examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986), incorporated by reference in its entirety.

Of course, any of the release retardants mentioned hereinabove may beutilized in any mixture or combination, either as a homogeneouscombination or in the form of a heterogeneous combination, e.g., as partof a layered formulation.

The sustained-release profile of the matrix formulations of theinvention can be altered, for example, by varying the amount ofretardant, e.g., hydrophobic polymer, by varying the amount ofplasticizer relative to hydrophobic polymer, by the inclusion ofadditional ingredients or excipients, by altering the method ofmanufacture, etc.

An additional portion of the sustain release carrier can be admixed orwet granulated with the agglomerated particles if desired. For example,if more sustain release carrier or more active ingredient is needed thanthat which can be spray dried due to solids content, then the additionalrequired amounts of the sustain release carrier or the active ingredientis added to the spray dried mixture and this mixture is then wetgranulated or directly compressed in to solid dosage forms i.e.,tablets.

The sustained-release matrix according to the invention providessustained-release of the active agent for a period of, e.g. about 8 toabout 24 hours or more.

Sustained-release carrier formulations, e.g., matrix formulations, maybe prepared in accordance with the present invention using any art-knowntechniques. The sustained-release carrier formulations may be prepared,e.g., melt-granulation, wet granulation, melt-extrusion, dry blending,wet-extrusion, or by other art-known techniques.

In preferred embodiments of the invention, the sustained-release matrixis prepared by wet-granulating the requisite amounts ofsustained-release carrier and augmented microcrystalline cellulose toform a moistened mass. Preferably, the sustained-release carrier andaugmented microcrystalline cellulose are in powder form. The moistenedmass is then screened and dried, e.g. using a fluid bed dryer. The driedgranulate may then be further screened to obtain a granulate within adesired uniform particle size. The dried granulate may then be dividedinto unit doses and encapsulated in a hard gelatin capsule, orcompressed into tablets of desired size and shape.

In other embodiments, a pre-manufactured sustained-release matrix isprepared to which the active agent is added. The mixture is thenwet-granulated as described above, and, e.g. compressed to form atablet. For example, a sustained-release matrix may be prepared byblending a mixture of xanthan gum, locust bean gum and an augmentedmicrocrystalline cellulose in powder form in a granulator, e.g., a highspeed mixer. A sufficient amount of water is added to the mixture, whichis further blended. The mixed product, which is now in the form of a wetmass, is removed from the granulator and dried, e.g. in a fluid beddryer. The dried granulation is screened to produce dried granuleswithin a desired particle size range. The sustained-release excipient isthen ready to be used as a sustained release matrix which is suitablefor direct compression with any active medicament to form asustained-release dosage form. Alternatively, the dried screenedgranules may be encapsulated in hard gelatin capsules to produce thefinal solid sustained-release dosage form.

Additional pharmaceutical processing aids such as lubricants, e.g.magnesium stearate may be added to the sustained-release carrier orsustained-release excipient prior to further processing.

The present invention specifically provides an improved process for thepreparation of a agglomerated solid dosage form, comprising: (1)preparing an aqueous slurry of (a) microcrystalline cellulose; (b) amicrocrystalline cellulose compressibility augmenting agent which (i)physically restricts the proximity of the interface between adjacentcellulose surfaces; (ii) inhibits interactions between adjacentcellulose surfaces, for example, via the creation of a hydrophobicboundary at cellulose surfaces; or (iii) accomplishes both (i) and (ii)above; and (c) an active agent; (2) thereafter drying the resultantaqueous slurry in a manner which inhibits quasi-hornification, therebyobtaining an agglomerated material which is directly compressible into asolid dosage form.

In a preferred embodiment the aqueous slurry is dried using a spraydrying technique. In yet another preferred embodiment the presentinvention provides a process wherein the compressiblility augmentingagent is a surfactant having an HLB of at least about 10. It is furtherpreferred that the compressiblility augmenting agent is a surfactanthaving an HLB of at least about 15. The most preferred compressiblilityaugmenting agent is a surfactant having an HLB from about 15 to about40. In yet another embodiment of the present invention thecompressibility agent is selected from sodium lauryl sulfate andpolysorbate.

In a further preferred embodiment of the improved process of the presentinvention the compressiblility augmenting agent is a silicon dioxideportion being derived from a silicon dioxide having an average primaryparticle size from about 1 nm to about 100 μm. It is particularlypreferred when the silicon dioxide is included in amount from about 0.1%to about 20% by weight, based on the weight of microcrystallinecellulose and the silicon dioxide is colloidal silicon dioxide.

Yet another preferred embodiment of the present invention provides thatthe surfactant is included in amount from about 0.1% to about 20% byweight, based on the weight of microcrystalline cellulose.

In yet another preferred embodiment of the present invention a sustainedrelease carrier is added into the aqueous slurry, and drying the aqueousslurry in such a manner as to obtain agglomerated sustained releaseparticles. Preferred sustained release carrier is selected from thegroup consisting of an alkyl cellulose, an acrylic polymer or copolymer,a cellulose ether, a cellulose ester, and mixtures thereof. In yetanother preferred embodiment it is preferred that the sustained releasecarrier is a natural or a synthetic gums.

The present invention further provides an improved process furthercomprising adding a film forming agent into the aqueous slurry, anddrying the aqueous slurry in such a manner as to obtain agglomeratedparticles having a film coating.

Also provided by the present invention is a process to compress thegranulate into tablets.

Yet another particularly preferred embodiment of the present inventionprovides a process wherein the solids content of the aqueous slurry isfrom about 0.5 to about 25%, by weight, the preferred solid content ofthe aqueous slurry be from about 15 to about 20%, by weight, and a

GENERAL DESCRIPTION OF THE PROCESS OF THE PRESENT INVENTION

The process of the present invention generally provides making anaqueous slurry by mixing at least two ingredients selected frommicrocrystalline cellulose, augmenting agent, sustain release carrierand an active agent in water and vigorously stirring the resultingaqueous mixture. This resulting aqueous slurry having intimatelycombined materials is then spray dried to provide an agglomeratedmaterial which is directly compressible into a solid dosage form.

What is claimed is:
 1. A process for the preparation of an agglomeratedmaterial solid dosage form, comprising preparing an aqueous slurrycomprising: (a) microcrystalline cellulose; (b) a microcrystallinecellulose compressibility augmenting agent comprising a highly polar dyeselected from the group consisting of 3,3′-[[1,1′Biphenyl]-4,4′-diylbis-(azo)]bis[4-amino-1-naphthalenesulfonic acid] disodiumsalt; disodium salt of 6-hydroxy-5[(2-4-sulfophenyl)azo]-2-naphthalenesulfonic acid); 5-oxo-1-(p-sulfophenyl)-4-[(p-sulfophenyl)azo]-2-pyrazoline-3-carboxylic acid,trisodium salt); disodium salt of1-p-sulphophenylazo-2-naphthol-6-sulfonic acid); trisodium-2-hydroxy-1-(4-sulfonato-1-naphthylazo) naphthalene-6, 8-disulfonate); disodium4,4′-(2,4- dihydroxy-5-hydroxymethyl-3, 3-phenylenebisazo)di(napthalene-1-sulfonate)); tetrasodium4-acetamido-5-hyroxy-6-[7-sulfonato-4-(4-sulfonatophenylazo)-1-naphthylazo]naphthalene-1,7-disulfonate); disodium4-hydroxy-3-(4-sulfanato-1- naphythylazo) Naphthalene-1-sulfonate);trisodium 2-hydroxy-1-(4-sulfonato-1- naphthylazo) naphthalene-3,6-disulfonate) and mixtures thereof which inhibits interactions betweencellulose surfaces via the creation of a hydrophobic boundary atcellulose surfaces; and (c) an active agent; and thereafter drying theresultant aqueous slurry utilizing a spray drying technique to obtain anagglomerated material which is then directly compressed into a tablet.2. The process of claim 1, wherein said compressibility augmenting agentfurther comprises a surfactant having an HLB of at least about
 10. 3.The process of claim 1, wherein said compressibility augmenting agentfurther comprises a surfactant having an HLB of at least about
 15. 4.The process of claim 1, wherein said compressibility augmenting agentfurther comprises a surfactant having an HLB of at least about 15 toabout
 40. 5. The process of claim 4, wherein said surfactant is sodiumlauryl sulfate.
 6. The process of claim 4, wherein said surfactant ispolysorbate.
 7. The process of claim 1, wherein said compressibilityaugmenting agent further comprises a silicon dioxide having an averageprimary particle size from about 1 nm to about 100 μm.
 8. The process ofclaim 7, wherein said silicon dioxide is included in an amount fromabout 0.1% to about 20% by weight, based on the weight ofmicrocrystalline cellulose.
 9. The process of claim 2, wherein saidsurfactant is included in an amount from about 0.1% to about 20% byweight, based on the weight of microcrystalline cellulose.
 10. Theprocess of claim 8, wherein said silicon dioxide is colloidal silicondioxide.
 11. The process of claim 1, further comprising adding asustained release carrier into the aqueous slurry, and drying theaqueous slurry in such a manner as to obtain agglomerated sustainedrelease particles.
 12. The process of claim 11, wherein said sustainedrelease carrier is selected from the group consisting of an alkylcellulose, an acrylic polymer or copolymer, a cellulose ether, acellulose ester, and mixtures thereof.
 13. The process of claim 11,wherein said sustained release carrier is selected from natural orsynthetic gums.
 14. The process of claim 1, further comprising adding afilm forming agent into the aqueous slurry, and drying the aqueousslurry in such a manner as to obtain agglomerated particles having afilm coating.
 15. The process of claim 1, further comprising compressingthe resultant granulate into tablets.
 16. The process of claim 11,further comprising compressing the resultant granulate into tablets. 17.The process of claim 14, further comprising compressing the resultantgranulate into tablets.
 18. The process according to claim 1, whereinthe solids content of the aqueous slurry is from about 0.5 to about 25%,by weight.
 19. The process according to claim 1, wherein the solidscontent of the aqueous slurry is from about 15 to about 20%, by weight.20. The process according to claim 11, wherein the solids content of theaqueous slurry is from about 0.5 to about 25%, by weight.
 21. Theprocess according to claim 11, wherein the solids content of the aqueousslurry is from about 15 to about 20%, by weight.
 22. The processaccording to claim 14, wherein the solids content of the aqueous slurryis from about 0.5 to about 25%, by weight.
 23. The process according toclaim 14, wherein the solids content of the aqueous slurry is from about15 to about 20%, by weight.
 24. A product according to claim
 1. 25. Aproduct according to claim
 11. 26. A product according to claim
 14. 27.The process according to claim 11, wherein a further amount of sustainedrelease carrier is admixed with said agglomerated sustained releaseparticles and the resulting mixture is compressed into tablets.
 28. Theprocess of claim 27, wherein said mixture is prepared via wetgranulation.
 29. The process of claim 27, wherein a further amount ofactive ingredient is also added.
 30. The process of claim 11, furthercomprising compressing said agglomerated sustained release particlesinto a tablet, and further applying an additional portion of saidsustained release carrier as a coating onto said tablet.
 31. The processof claim 1, wherein the resultant aqueous slurry is dried in a mannerwhich inhibits quasi-hornification.
 32. The process of claim 1, whereinsaid composition comprises from about 0.1 to about 20% of said highlypolar dye based on the weight of microcrystalline cellulose.
 33. Theprocess of claim 1, comprising utilizing a spary drying technique to drythe aqueous slurry.
 34. The process of claim 1, wherein said highlypolar dye has an HLB of at least about
 10. 35. The process of claim 1,wherein said highly polar dye has an HLB of at least about
 15. 36. Theprocess of claim 1, wherein said highly polar dye has an HLB of at leastabout 15 to about 40.